Inflammatory bowel disease and prostate cancer: from epidemiological controversy to mechanistic hypotheses

Inflammatory bowel disease (IBD) is a chronic systemic inflammatory disorder with rising global prevalence. Epidemiological evidence linking IBD to prostate cancer (PCa) risk remains conflicting. Observational cohorts suggest a possible elevated risk, though this remains uncertain and may be influenced by detection bias. Mechanistically, chronic intestinal inflammation may indirectly promote prostate carcinogenesis through systemic cytokines, immune cell infiltration, and activation of the NF-κB/STAT3/AKT signaling pathway, coupled with oxidative stress and DNA damage. The gut-prostate axis, driven by microbial dysbiosis, represents another emerging pathway. Notably, GCPII independently identified as PSMA in prostate cancer and as FOLH1 in inflamed intestinal mucosa, is upregulated in both contexts, suggesting a molecular bridge linking intestinal inflammation to prostate malignancy. However, standardized screening protocols, validated risk stratification models, and targeted prevention strategies remain lacking for the IBD population. This review synthesizes current epidemiological and mechanistic evidence, identifies surveillance bias as a primary confounder, and proposes the GCPII--glutamate--mGluR1 axis as a hypothetical yet testable mechanistic framework. We further advocate for inflammation burden-based risk stratification as a research priority, while acknowledging that this approach remains hypothetical and requires prospective validation before clinical implementation.